Dr. He or: How I Learned to Stop Worrying and Love the Genetic Engineering – China, USA and the Nobel Prize for CRISPR

by Markus Pohlmann and Liu YuanYuan

Nowadays, Mary Shelley would be happy and terrified at the same time. Happy about how up to date her novel still is, terrified about how little we have learned from it. On the contrary: experiments similar to that of Frankenstein are numerous, and their results are sometimes bitter-sweet. Like in the case of the toddlers‘ Lulu and Nana, subject to genetic manipulations of the Chinese scientist He Jiankui. We have already reported on this topic (for further, see the blog post Gattaca in China: The Birth of the first genetically engineered Humans). Even though the genetic manipulation was probably not successful in this particular case, the children are now in our world, and one day they may change the gene pool of humanity. How should we deal with matters like these? Should and can we protect the gene pool of humankind? What if Nana and Lulu give birth to children one day? These are just some troublesome issues that arise in this new human genetic era of genetic engineering. Although Nana and Lulu are just the tips of the iceberg, behind this one case appears to be a rapidly growing gene modification system, as reported by numerous scandals in recent years.

CRISPR/Cas-Complex with DNA; CRISPR-associated protein Cas9 (white) from Staphylococcus aureus; source: wikipedia.org

Human genetic modification as a scientific method certainly promises valuable things in the fight against many diseases as well. For this reason, Emmanuelle Charpentier and Jennifer Doudna received this year’s Nobel Prize in Chemistry for their genome editing system CRISPR/Cas9. Charpentier, the French scientist (currently working in Germany) and Doudna, an American professor from Berkeley University, were awarded the prize despite ongoing patent disputes with a Chinese scientist at MIT Feng Zhang. Their method made it possible to alter the genome of plants, animals, and humans with a great amount of precision. The hopes are now higher than ever for curing hereditary and other diseases in the future. There are already many positive prospects – two female infants from Great Britain who had leukemia and treated with a genetic engineering method showed no more signs of cancer one year later. Furthermore, American scientists have already inactivated the HIV-1 gene with a gene-editing system. In general, there are more than 10,000 diseases that are caused by defective genes, which implies a massive field of use for genetic modification amounting to a billion-dollar business for the pharmaceutical companies and biotech industry.

DNA repair after double-stranded break; source: wikipedia.org

The Nobel Prize

This is what this year’s Nobel Prize for Chemistry stands for. It shows how the USA and China are currently staking their claims in the gold rush for CRISPR and, at the same time, have developed a profitable division of labor in the competition for the usage of the „gene scissors“. Notably, the ongoing patent disputes between the two Nobel Prize winners and their companies with Feng Zhang record the furious battle for claims in the application of CRISPR and the international division of labor in the background. While the method’s ideas came from the two Nobel laureates, Feng Zhang and his team are profoundly active in genetic engineering usage. All three scientists stand for four start-ups, behind which the pharmaceutical companies have been prominently gathering. Red, green, and white gene technologies are on the agenda; numerous patents are held, and the stock market runs hot. The proclamation here is an investment in Nobel Prize technologies with promising high returns.[1] According to one of the most prominent financial websites on the web, CRISPR Therapeutics has delivered the best stock performance to date. Although they have only generated revenues in the range of a few million U.S. dollars jet. The commercialization of the research results is still in its beginnings. However, in the medium to long term, their stock market price could boom if the pipeline development meets the expectations placed in it (https://www.fool.de/2020/10/11/nobelpreis-technologien-in-die-man-renditestark-investieren-kann/).

Own illustration based on: https://www.nzz.ch/wissenschaft/bericht-zu-chinesischen-designbabys-kein-durchbruch-ld.1526268; source: wikipedia.org

Behind the whole narrative an international division of labor stands out, which is typical for the entire commercialization of CRISPR/Cas 9. On the one hand, the USA and China are in a fierce competition, and on the other hand, when it comes to opening up the legal scope of grey areas for genetic modification, they are in a tight collaboration – a kind of „regime shopping“. In fact, He Jiankui is not the only scientist in China who crossed ethical and legal standards concerning human experiments, experiments with primates, and human genetic modification. In 2017, Professor Ren Xiaoping of Harbin Medical University in China performed the world’s first head replacement surgery on cadavers. An experiment in China, in 2019, improved monkeys‘ intelligence to the human level using the gene-editing tool. The media reports that Chinese scientists have already genetically modified several macaques and tested their intelligence. The study published in the National Science Review in Beijing reports that researchers from the Kunming Institute of Zoology along with the Chinese Academy of Sciences, the University of North Carolina in the U.S., and some other research institutions, have already successfully created 11 transgenic rhesus monkeys carrying the human MCPH1 gene copies. At least in short-term memory, improvements are said to have been achieved.

China appears regularly as a „hotspot“ in genetic engineering experiments, questioning the ethical consensus over the years. Despite all competition, it seems that American scientists had found a new playground here which is even more generous than in their home country.

Dr. He and the genetic modification system

During the He Jiankui case investigation, it became clear that Dr. He had not carried out his human genetic modification in secret. Instead, it appears that many American scientists knew about it and were even somehow involved in the experiments. George Church, geneticist and a CRISPR pioneer at Harvard University, says Dr. He had rather a big company, and it would be too easy to pass himself as a villain or single “bad apple” off. His companionship also included three professors from Stanford University: Stephen Quake, Professor of Applied Physics and Bioengineering; William Hurlbut, Professor of Bioethics; and Matthew Porteus, Professor of Pediatrics. Also involved were Medical School professors at the University of Massachusetts, including Nobel Laureate Craig Mello and He’s doctoral advisor, Professor Deem, from Rice University. Shortly before the experiment, William Hurlbut had even intense discussions with Dr. He for months. Hurlbut also knew the exact date of intervention and the actual date of birth of the third genetically manipulated child. Professor Deem from Rice University is listed as a senior author in an unpublished research manuscript, and Stephen Quake had emailed He: „Wow, That’s quite an achievement! Hopefully, she will carry to term…“.

He Jiankui speaking at the Second International Summit on Human Genome Editing; source: wikipedia.org

A closer look at the case of Dr. He (or: How I learned to stop worrying and to love genetic engineering) shows the line-crossing interaction of American scientists and the implementation of their ideas in China. After all, Viktor Frankenstein in Ingolstadt wasn’t a lone wolf, and neither was Dr. He. And despite all the competition, it is clear that close scientific cooperation in the grey domains of „genetic engineering“ is rather the rule than the exception. The environment here plays a fundamental role in this „social learning“ of deviations from the rules. In the „social cocoon“ of such a pioneering science, one receives recognition for transgressions that promote interest in knowledge and marketing opportunities. For the fact that these go hand in hand is an essential part of this system.

Global Genetic Engineering Chain 

While research on primates and humans is becoming more difficult in Europe and the USA, China is rushing to apply the latest high-tech DNA tools. The scientists there have already created monkeys modified with the gene-editing tool CRISPR. Furthermore, in January 2020, one Chinese institute has reported having created half a dozen clones of a monkey with a severe mental disorder.

In the course of globalization, it is easy to see that regulatory differences between countries and organizations are being used in a kind of „regime shopping“ to accomplish cutting-edge experiments, even if these are located in an ethical and a legal grey area. Besides that, the patent competition between the two leading genetic engineering nations, the USA and China, shows how the global value chain is being built.

In the utilization battle for CRISPR/Cas 9, the USA was leading in 2018 with 872 patents, followed by China with 858. European countries have only 194 such patents pending, followed by the Republic of Korea (75 patents) and Japan (48 patents). Often it is universities or research institutes that hold the patents, but in the meantime, many private companies also maintain them. In China, unlike in the USA, the patent holders are almost exclusively Chinese citizens. They rarely extend the patents to other countries. Instead, they seem to labor to secure the Chinese market’s claims in the dense patent landscape. In this case, all other countries have to pay high license fees to operate the Chinese market. The national interest behind the flood of patent applications for CRISPR is easy to see here.

Source: Jacqueline, M-L, Kuntz, M. &. Ricroch, A. E. (2019). Worldwide CRISPR patent landscape shows strong geographical biases. Nature Biotechnology 37: 613–620. doi: https://doi.org/10.1038/s41587-019-0138-7.

Although China focuses on green genetic engineering and providing food for the world’s most populated country, they already hold more patents on red genetic engineering than the USA. Many of these patents are usage-oriented genetic engineering patents, which enableChina to position itself in the „Global Genetic Engineering Chain“ as a „permissive“ workshop and a genetic engineering experimental laboratory.

The gray areas and the judgment  

He Jiankui was convicted in 2019 for the „illegal practice of medicine“ in China. The sentence provided a prison term of three years and a fine of 3 million RMB (approx. 380,000 Euro). The punishment is milder than expected by the international press. Three-years-imprisonment is the lowest penalty in China for the crime of „illegal practice of medicine,“ and 3 million RMB fine is equivalent to a relatively small, 50 m2 apartment in Shenzhen.

This sentence is even more astonishing if we learn the possible health consequences of the state of already born twins and the third baby. Unwanted genetic effects can easily occur, leading to potential health problems. These risks are well known. For example, four out of 10 children who experienced gene therapy in France in 2002 have developed leukemia. The youngest child even died of leukemia five years after gene therapy.

In light of the case, the „wisdom“ of the party and government in China is once again becoming apparent. Tolerating individual breaches of rules by scientists seems to be in consonance with the national interest. Taking risks, and imposing milder penalties to avoid obstructing the avenue of exploration on new human genetic territory iseverything for China’s leading position in scientific research. Nevertheless, for the Chinese government, Dr. He is only a scientist who aspires „personal fame and advantage.“ To sanction him quickly allows them to save their face without sending out signals of deterrence. On the question – How can the gene pool of humanity be protected? The party and government in China have their answer anyway. If the party and government want to, they can easily arrange for the sterilization of Nana and Lulu, for example – something they they might have already done.

A scene from Stanley Kubrick’s movie „Dr. Strangelove or: How I Learned to Stop Worrying and Love the Bomb“ (1964); source: wikimedia.org

Where do we stand now?

The critical question is no longer whether we will cross a red line with gene modification, because this happened a long time ago. The risks are beyond the discussion. This issue is something that perhaps still concerns us social scientists or ethicists and lawyers. Genetic engineering has spread at high-speed in recent years, and the USA and China have already staked out many claims. Because that’s what it is all about at the moment: the claims and marketing opportunities in a multi-billion-dollar business. The Nobel Prize for Chemistry stands exactly for that. For the rigorous dispute over the claims and for the competition between China and the USA. However, this should not conceal the fact that their cooperation and labor division are workingjust fine. On the one hand, American biotechnology and science „at the cutting edge of new knowledge“ provide new genetic modification ideas. On the other hand, China is the „hardly constitutional state-controlled workbench“, the experimental laboratory in which the gene pool of humanity is released for „genetic engineering“ – as long as the party and government have their hands on it and the discoveries claims can be protected in China.

In this „Global Genetic Engineering Chain,“ the gene pool of humanity is currently more or less available for modification, with many possible healing effects, but also with just as many Frankenstein elements, which make even the wildest science-fiction Hollywood fluff look pale.

Source: Amazon.com

And soon, we all can play with the gene pool of humanity ourselves: there is a CRISPR „basic tool-kit“ already on the market, available at Amazon.com for just 169 USD, only a children’s kit is still missing.

References:

[1] The „red“ biotechnology covers two areas: Biotech drugs and biomedical technology; „green“ biotechnology deals with plants and „white“ biotechnology with the improvement of industrial production processes.

Sources and further literature:

CBS Radio (2019). Scientist jailed for making gene-edited babies had ‚idealistic‘ intentions, says colleague. CBC Radio (30/12/2019). https://www.cbc.ca/radio/asithappens/as-it-happens-monday-edition-1.5410647/scientist-jailed-for-making-gene-edited-babies-had-idealistic-intentions-says-colleague-1.5410649. Accessed on 15/10/2020.

Cohen, J. (2019). The untold story of the ‚circle of trust‘ behind the world’s first gene-edited babies. Science (01/08/2019). https://www.sciencemag.org/news/2019/08/untold-story-circle-trust-behind-world-s-first-gene-edited-babies. Accessed on 15/10/2020.

DeAngelis, A. (2020). CRISPR creators, startup founders win Nobel Prize. Bizwomen.https://www.bizjournals.com/bizwomen/news/latest-news/2020/10/crispr-creators-startup-founders-win-nobel-prize.html?page=all. Accessed on 15/10/2020.  

Guarino, B. (2020). Nobel Prize in chemistry awarded to two women who developed CRISPR, a revolutionary gene-editing tool. The Washington Post (07/10/2020). https://www.washingtonpost.com/science/2020/10/07/nobel-prize-chemistry/. Accessed on 15/10/2020. 

Hacein-Bey-Abina, S. et al. (2014). A Modified γ-Retrovirus Vector for X-Linked Severe Combined Immunodeficiency. The New England Journal of Medicine 371, (15): 1407–1417. doi:10.1056/NEJMoa1404588. 

Luo, X. et al. (2019). Trio deep-sequencing does not reveal unexpected mutations in Cas9-edited monkeys. bioRxiv 339143. doi: https://doi.org/10.1101/339143

Mak, E. (2020). Genome editing startup Edigene closes $67M series B to push pipeline to clinic. BioWorld (13/10/2020). https://www.bioworld.com/articles/498889-genome-editing-startup-edigene-closes-67m-series-b-to-push-pipeline-to-clinic?v=preview. Accessed on 15/10/2020.  

Ouagrham-Gormley, S. B. & Vogel, K. M. (2020). Follow the money: What the sources of Jiankui He’s funding reveal about what Beijing authorities knew about illegal CRISPR babies, and when they knew it. Bulletin of the Atomic Scientists 76 (4): 192-199. doi: 10.1080/00963402.2020.1780726

Regalado, A. (2019). Drittes CRISPR-Baby in China geboren? Heise online (24/07/2019). https://www.heise.de/hintergrund/Drittes-CRISPR-Baby-in-China-geboren-4477487.html. Accessed on 15/10/2020.

Regalado, A. (2019). Schlaue Affen durch menschliche Gene? Heise online (23/04/2019). https://www.heise.de/hintergrund/Schlaue-Affen-durch-menschliche-Gene-4403169.html. Accessed on 15/10/2020.

Rinde, M. (2019). The Death of Jesse Gelsinger, 20 Years Later. Distillations. Science History Institute (04/06/2019). https://www.sciencehistory.org/distillations/the-death-of-jesse-gelsinger-20-years-later. Accessed on 15/10/2020.

Saey, T. H. (2019). CRISPR enters its first human clinical trials. ScienceNews.https://www.sciencenews.org/article/crispr-gene-editor-first-human-clinical-trials. Accessed on 15/10/2020.  

Shi, L. et al. (2019). Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development. National Science Review 6 (3): 480-493. doi: https://doi.org/10.1093/nsr/nwz043.

Steinbuch, Y. (2017). World’s first human head transplant a success, professor says. New York Post (17/11/2017). https://nypost.com/2017/11/17/professor-claims-doctors-successfully-performed-human-head-transplant/. Accessed on 15/10/2020.  

Wu, K. J., Zimmer, C. & Peltier, E. (2020). Nobel Prize in Chemistry Awarded to 2 Scientists for Work on Genome Editing. New York Times (07.10.2020). https://www.nytimes.com/2020/10/07/science/nobel-prize-chemistry-crispr.html. Accessed on 15/10/2020. 

Xin, L. U. O., Min, L. I. & S. Bing, U. (2016). Application of the genome editing tool CRISPR/Cas9 in non-human primates. Zoological Research 37 (4): 241–219. doi: 10.13918/j.issn.2095-8137.2016.4.214.


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